Methotrexate (MTX) has activity in transitional cell carcinoma (TCC) in man and some have suggested an advantage of high-dose methotrexate versus the standard dose in controlling tumor growth and prolonging survival. MBT-2, a poorly differentiated TCC induced by the carcinogen FANFT, is both grossly and histologically similar to human TCC and has been used as an animal model. One hundred twenty C3H/HE female mice were injected in the hind limb with 7.5 X 10(4) MBT-2 tumor cells. When palpable tumors developed in all animals, therapy was initiated. Animals were randomized into a control group and nine treatment groups as follows: cisplatin (DDP), MTX32 mg, MTX50 mg, MTX80 mg, DDP + MTX32, MTX50 + Leucovorin, MTX80 + Leucovorin, DDP + MTX50 + Leucovorin, DDP + MTX80 + Leucovorin. The combination of MTX50 mg with Leucovorin + DDP and DDP alone were the two most effective regimens in controlling tumor growth and prolonging survival. No statistically significant difference was observed between the group treated by high-dose MTX alone and those treated by low-dose MTX. No toxicity was observed even when high doses of MTX were used.